1. Modeling Ca2+ Feedback on a Single Inositol 1,4,5-Trisphosphate Receptor and Its Modulation by Ca2+ Buffers 
Jianwei Shuai, John E. Pearson, Ian Parker 
Biophysical Journal 
Volume 95, Issue 8, Pages (October 2008)
DOI: /biophysj
Copyright © 2008 The Biophysical Society Terms and Conditions

2. Figure 1
IP3R subunit model and the multiple-grid-size method. (A) Schematic diagram of the IP3R channel subunit model. The subunit has an IP3 binding site, an activating Ca2+ binding site, and an inhibitory Ca2+ binding site. Bold arrows indicate the binding of ligands to different sites, and the shaded regions indicate conformations referred to as active, inactive (without Ca2+ bound to the inhibitory site), and inhibited (with Ca2+ bound to the inhibitory site). (B) In the model, we use a multiple-grid-size method to discretize the cytosolic space. An overlap region is used to connect the concentration in different regions. So concentration C0[2] at R0[2] is an average of the concentration C16[1] at R16[1] and C17[1] at R17[1].
Biophysical Journal  , DOI: ( /biophysj )
Copyright © 2008 The Biophysical Society Terms and Conditions

3. Figure 2
[Ca2+] distribution around the channel mouth. (A and B) Spatial and temporal distributions of cytosolic [Ca2+] around the pore of an IP3R channel in the absence of any Ca2+ buffer. The channel is assumed to open for 20ms, carrying a Ca2+ current of 0.2 pA. (A) Spatial [Ca2+] distribution as a function of distance from the channel pore at the instant before channel closes (T=0) and at different times (indicated in ms) after closing. (B) Temporal changes in [Ca2+] at the channel pore (R=0⁡nm) and at different distances (indicated in nm) from the pore. (C and D) Corresponding simulations with stationary Ca2+ buffer in the cytosolic space. (C) Spatial [Ca2+] distributions at T=0 and at different times after the channel closed, for a stationary buffer concentration ST=300μM. (D) Temporal traces of [Ca2+] at channel pore for different stationary buffer concentrations as indicated in μM.
Biophysical Journal  , DOI: ( /biophysj )
Copyright © 2008 The Biophysical Society Terms and Conditions

4. Figure 3
(A) Representative dynamics of the monomeric model with [Ca2+] clamped at 0.05μM and [IP3]=10μM. The upper panel illustrates bursting behavior of channel states (0=closed, 1=open) on a slow timescale, and the second panel shows channel gating during a single burst on an expanded timescale. The third panel shows local [Ca2+] at the channel pore, and the lower panel shows transitions between different subunit states during the burst. (B) Corresponding examples of channel, [Ca2+] and subunit dynamics for the case where Ca2+ ions flow through the channel. No Ca2+ buffers are present. [IP3]=10μM. (C) Monomeric IP3R model dynamics with Ca2+ flux in the presence of stationary buffer ST=300μM in the cytosolic compartment. [IP3]=10μM.
Biophysical Journal  , DOI: ( /biophysj )
Copyright © 2008 The Biophysical Society Terms and Conditions

5. Figure 4
Statistical dynamics of the monomeric IP3R model. (A) Channel open probability PO as a function of [IP3]. The solid line is obtained with [Ca2+] clamped at 0.05μM; the squares are simulation results with Ca2+ feedback in the absence of any Ca2+ buffers, and the stars are results with Ca2+ feedback in the presence of immobile cytosolic buffer ST=300μM. (B and C) Cumulative probabilities of Ca2+ binding to the activating Ca2+ site (B) and to the inhibitory Ca2+ site (C) of the monomeric model at increasing times latency after the channel closes. [IP3]=10μM. In both panels, the dashed lines are obtained with [Ca2+] clamped at 0.05μM; the solid curves are calculated with Ca2+ feedback in the absence of buffer; and the dotted curves are with Ca2+ feedback in the presence of stationary buffer ST=300μM.
Biophysical Journal  , DOI: ( /biophysj )
Copyright © 2008 The Biophysical Society Terms and Conditions

6. Figure 5
Dynamics of the complete, multimeric IP3R model. (A) Representative channel kinetics with [Ca2+] clamped at 0.05μM. The upper panel illustrates bursting behavior of channel states on a slow timescale; the second panel shows local [Ca2+] at the channel pore and, in gray overlay, channel openings during a single burst at an expanded timescale; the lower panel shows the number of subunits in the active state before, during, and after the burst. (B) Panels represent the states of the four subunits corresponding to the burst shown in A. (C and D) Corresponding examples of channel gating, local [Ca2+], and subunit states with Ca2+ feedback in the absence of any Ca2+ buffer. (E and F) Corresponding examples of channel gating, local [Ca2+], and subunit states with Ca2+ feedback in the presence of stationary buffer ST=300μM. In all examples, [IP3]=10μM.
Biophysical Journal  , DOI: ( /biophysj )
Copyright © 2008 The Biophysical Society Terms and Conditions

7. Figure 6
Statistical dynamics of the multimeric IP3R channel in the absence of Ca2+ buffer, exploring separately the effects of Ca2+ feedback on the activating and inhibitory binding sites located at the channel pore. (A–C) Panels show, respectively, the mean channel closed time τC, the mean open time τO, and the open probability PO as functions of [IP3]. (D–F) Burst dynamics of the channel, derived by setting a criterion of 20ms to discriminate between short interburst closings and longer intraburst intervals. Panels show, respectively, mean interburst durations, mean intraburst intervals, and mean burst durations as functions of [IP3]. In all panels, the families of curves were obtained by either fixing [Ca2+] at the activating and/or inhibitory binding sites at the resting level, or by allowing Ca2+ feedback via flux through the channel. Specifically, squares represent both activating and inhibitory Ca2+ binding sites clamped at [Ca2+]=0.05μM; stars represent inhibitory Ca2+ binding sites clamped; triangles represent Ca2+ feedback on inhibitory sites with activating sites clamped; and circles represent Ca2+ feedback on both activating and inhibitory binding sites.
Biophysical Journal  , DOI: ( /biophysj )
Copyright © 2008 The Biophysical Society Terms and Conditions

8. Figure 7
Distribution of open (A) and closed time durations (B) for the multimeric IP3R model with Ca2+ feedback in the presence of immobile buffer. ST=300μM and [IP3]=10μM.
Biophysical Journal  , DOI: ( /biophysj )
Copyright © 2008 The Biophysical Society Terms and Conditions

9. Figure 8
Modulation of multimeric IP3R model dynamics by stationary buffer. (A–C) Panels show, respectively, the mean closed time τC, mean open time τO, and mean open probability PO as functions of ST. (D–F) Corresponding changes in channel dynamics as functions of Ca2+ binding rate to immobile buffer at ST=300μM. Here [IP3]=10μM. In all cases, Ca2+ feedback is operational, with the activating and inhibitory Ca2+ binding sites located either at the channel pore (R=0⁡nm) or at the edge of the IP3R (R=15⁡nm). Specifically, stars represent both activating and inhibitory Ca2+ binding sites at R=0 nm; circles represent activating binding sites at R=15 nm and inhibitory sites at R=0 nm; squares represent activating sites at R=0 nm and inhibitory sites at R=15 nm; and triangles represent both active and inhibitory Ca2+ binding sites at R=15 nm.
Biophysical Journal  , DOI: ( /biophysj )
Copyright © 2008 The Biophysical Society Terms and Conditions

10. Figure 9
Tetrameric IP3R model dynamics as a function of [IP3] in the presence of stationary buffer. (A–C) Panels show, respectively, the mean closed time τC, mean open time τO, and mean open probability PO as functions of [IP3] at ST=300μM. The same notations as in Fig. 8 are used here.
Biophysical Journal  , DOI: ( /biophysj )
Copyright © 2008 The Biophysical Society Terms and Conditions

11. Figure 10
Modulation of multimeric IP3R model dynamics by mobile buffer. (A–C) Panels show, respectively, the mean closed time τC, mean open time τO, and mean open probability PO as functions of diffusion coefficient of the mobile buffer DMCa for MT=300μM. (D–F) Corresponding changes in channel dynamics as functions of mobile buffer concentration MT for DMCa=15μm2/s. [IP3]=10μM. The same notations as in Fig. 8 are used here.
Biophysical Journal  , DOI: ( /biophysj )
Copyright © 2008 The Biophysical Society Terms and Conditions